Clostridium difficile is one of the most frequently recognized bacterial causes of diarrheal disease in hospitalized adults in industrialized countries. The microorganism can be acquired nosocomially and is present in environmental sources. Antibiotic associated colitis and pseudomembranous colitis are frequently associated with cytotoxigenic Clostridium difficile. The frequency of Clostridium difficile toxin associated with antibiotic associated colitis is 50-80% and with pseudomembranous colitis is 90-100%. Despite available treatment for antibiotic associated colitis and pseudomembranous colitis, relapses occur in 20-25% of patients. Vancomycin and metronidazole can be effective, but are subject to relapse after the use of the drugs may occur.
Clostridium difficile produces two toxins, A (enterotoxic) and B (cytopathic), the former (Toxin A) being implicated in the pathogenesis of pseudomembranous colitis. Toxin A causes hemorrhagic fluid accumulation associated with mucosal damage and a cytopathic effect in tissue culture cells. In experimental animals such as rabbits, toxin A causes hemorrhagic fluid secretion and cell damage in ligated intestinal segments of loops, and is considered to be the cause of antibiotic-associated colitis in experimental hamsters and in people.
Toxin B is a more potent cytotoxin than toxin A, but it has no enterotoxic activity. It has been reported that the toxin A is important in the pathogenesis of Clostridium difficile disease. In animal models of the disease, Clostridium difficile culture supernatant filtrate or purified toxin A causes mucosal lesions characteristic of antibiotic-associated colitis. In human disease, as well as in animal models, a spectrum of mucosal changes ranging from nonspecific colitis (with or without diarrhea) to severe disease with complete mucosal necrosis has been described in prior literature.
Antibiotics, including vancomycin or metronidazole, directed against C. difficile, or anion exchange resins that bind the toxins of C. difficile, including cholestyramine, have been used to treat C. difficile diarrhea. However, the antibiotics prolong carriage of C. difficile and relapses are common and resins are not always well tolerated.
PAF inhibitors have been have been found to be effective in treating Inflammatory Bowel Disease (IBD) when administered 4-7 days after the induction of colitis. The PAF inhibitor BN52021, however, shows no effect in the first four days. Chemical Abstracts 110:190302k (1989). IBD is distinct from the specific Clostridium difficile toxin-induced antibiotic associated acute colitis. IBD, including Crohn's disease, is a chronic, recurring, granulomatous inflammatory process that is largely related to host susceptibility. C. difficile diarrhea is a specific, acute, toxinsmediated diarrhea that can occur in any individual and does not recur over many years as is characteristic of IBD. Clostridium difficile is defined as "a species that is part of the normal colon flora in human infants and sometimes in adults. It sometimes produces a toxin that causes pseudomembranous enterocolitis in patients receiving antibiotic therapy" Dorland's Illustrated Medical Dictionary, W. B. Saunders Co., Philadelphia, Pa., 27th Edition, 1988, p. 348. Pseudomembranous enterocolitis is defined as "an acute inflammation of the bowel muscosa with the formation of pseudomembranous plaques overlying an area of superficial ulceration, and the passage of the pseudomembranous material in the feces; it may result from shock and ischemia or be associated with antibiotic therapy. Dorland's Illustrated Medical Dictionary, supra, p. 560. Crohn's disease is defined as "a chronic granulomatous inflammatory disease of unknown etiology, involving any art of the gastrointestinal tract from mouth to anus, but commonly involving the terminal ileum with scarring and thickening of the bowel wall; it frequently leads to intestinal obstruction and fistula and abscess formation and has a high rate of recurrence after treatment." Dorland's Illustrated Medical Dictionary, supra, p. 484. IBD is, to an extent, susceptible to control by diet, fitness and stress reduction. Eating Right for a Bad Gut: The Complete Nutritional Guide to Ileitis, Colitis, Crohn's Disease & Inflammatory Bowel Disease, Dr. James Scala, Penguin.